Cohort Profile: The Pregnancy and Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study

Cohort Profile: The Pregnancy and Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study Why was the study set up? Type 2 diabetes (T2DM) contributes significantly to the mortality gap between Indigenous and non-Indigenous Australians, with the onset of diabetes occurring at a younger age among Indigenous Australians.1 We respectfully acknowledge the two Indigenous populations of Australia, the Aboriginal and Torres Strait Islander peoples, who are referred to as Indigenous people in this paper. Thus T2DM is increasingly reported in Indigenous children and youth, and also prior to pregnancy among Indigenous women. Indigenous women are 10 times more likely to have T2DM in pregnancy and 1.5 times more likely to have gestational diabetes (GDM) than non-Indigenous women.2 The intergenerational impact of T2DM on Indigenous communities is of great concern, as offspring of an intrauterine environment exposed to hyperglycaemia in pregnancy (HIP) are at significantly higher risk of obesity and diabetes later in life. For example, among Pima Indian peoples, children born after their mother was diagnosed with HIP were reported to have significantly higher body mass index (BMI) and 4-fold higher diabetes risk than their siblings born prior to diagnosis.3 Prevention strategies implemented during early life are likely to be the most effective in addressing this epidemic among Indigenous Australians. In this context, HIP (which includes both GDM and pre-existing type 2 diabetes in pregnancy) may identify a group among Indigenous mothers and children who will specifically benefit from targeted early intervention, to reduce future risk and burden of chronic disease in this high-risk population. The Barker hypothesis proposed that inadequate nutrition in utero and in early infancy contributes to increased chronic disease risk later in life, including diabetes.4 This is known as the fetal programming or Developmental Origins of Health and Disease hypothesis. Paradoxically, the HIP that contributes to over-nutrition in the developing offspring is also associated with higher chronic disease risk.5,6 Indigenous communities in the Northern Territory (NT) experience the double burden of increasing HIP rates and inadequate nutrition. Hence it is pivotal to understand the complex interplay of these issues on offspring outcomes, to inform clinical guidelines in order to reduce future risk of chronic disease in the high-risk Indigenous Australian population. The PANDORA Study is a prospective, observational pregnancy and birth cohort study of 1140 women and 1170 children, with detailed pregnancy and birth data collected, plus neonatal anthropometric measurements and matched biospecimens. The primary aim of the study is to assess demographic, clinical, socioeconomic and biochemical factors that may contribute to key maternal and neonatal birth outcomes associated with HIP in the high-risk Indigenous Australian population. The PANDORA Study also assesses relevant long-term clinical and cardiometabolic outcomes for both mothers and their infants, to provide reliable information around future health risk. The follow-up of mothers and children in PANDORA is planned with current consent for follow-up until 12 years of age/postpartum. Following this, participants will be approached for assent/consent for ongoing follow-up. The PANDORA Study sits within the Northern Territory (NT) Diabetes in Pregnancy Partnership that has established the NT Diabetes in Pregnancy Clinical Register and has worked with health services to improve HIP models of care, contributing to improved integration, communication and care coordination.7,8 Who is in the sample? The NT of Australia covers a large geographical area with a relatively small population of approximately 240 000.9 This population is the youngest in Australia with a median age of 31.8 years, which is 6 years younger than the national median. The NT also has the highest proportion of Aboriginal and Torres Strait Islander people at 30%, representing 10% of the total Australian Indigenous population. In 2013, 31% of babies born to NT mothers were Indigenous compared with 6% among all babies born in Australia.10,11 Most Indigenous women (approximately 60%) live in rural or remote NT and receive antenatal care in their own communities.10 Local midwives, remote medical practitioners and general practitioner obstetricians provide antenatal care with support from outreach specialist obstetricians, allied health professionals and multidisciplinary input as available. Of all births in the NT, 98% occur within five hospitals. Women diagnosed with HIP were invited from the NT Diabetes in Pregnancy Clinical Register to participate in PANDORA. Women without HIP were recruited from antenatal clinics. During the course of the study, the GDM diagnostic guidelines were changing both in Australia and internationally. Between 2012 and 2014, there was a gradual increase in implementation of new guidelines throughout the NT. Hence women with GDM were diagnosed by either the 1999 Australian Diabetes in Pregnancy Society (ADIPS)12 guidelines, or a universal 75-g oral glucose tolerance test (OGTT) and revised glucose cut-points as recommended by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG)13 and the World Health Organization (WHO).14 Of the cohort, 10.3% satisfied only the ADIPS glucose thresholds, 11.5% satisfied only the WHO glucose thresholds and 76.6% satisfied both. Of note, Indigenous women with GDM in PANDORA were more likely to have oral glucose tolerance test (OGTT) results suggestive of possible undiagnosed T2DM (Indigenous vs non-Indigenous women, 19.3% vs 7.2%, P < 0.001, defined as fasting plasma glucose  ≥ 7.0 mmol/L or 2-h plasma glucose  ≥ 11.1 mmol/L or HbA1c  ≥ 6.5%).14 The PANDORA eligibility criteria are outlined in Table 1. The 5-year recruitment phase was completed in February 2017. A comparison of women with HIP in PANDORA and women on the Clinical Register is presented in Table 2. Note that some remote Indigenous women were ineligible for inclusion in the study before March 2015, as community consultation (a prerequisite for participation) was not completed with some Aboriginal Community Controlled Health Organizations. Targeted recruitment occurred in 2016. The PANDORA cohort at birth comprises 1140 women (905 with HIP and 235 without, 46.5% Indigenous women) and 1170 babies (including 16 twin sets). Table 1 Eligibility criteria Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years NT, Northern Territory. a Women with GDM were diagnosed by either the 1999 Australian Diabetes in Pregnancy Society (ADIPS)12 guidelines, or a universal 75-g oral glucose tolerance test (OGTT) and revised glucose cut-points as recommended by International Association of the Diabetes and Pregnancy Study Groups (IADPSG)13 and the World Health Organization (WHO).14 Table 1 Eligibility criteria Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years NT, Northern Territory. a Women with GDM were diagnosed by either the 1999 Australian Diabetes in Pregnancy Society (ADIPS)12 guidelines, or a universal 75-g oral glucose tolerance test (OGTT) and revised glucose cut-points as recommended by International Association of the Diabetes and Pregnancy Study Groups (IADPSG)13 and the World Health Organization (WHO).14 Table 2 Comparison between women with HIP in PANDORA and the NT Diabetes in Pregnancy Clinical Register Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 a Including women with GDM and T2DM only. Women without HIP (n = 235) have not been included. Women with T1DM have been excluded from PANDORA (n = 19) and the Clinical Register (n = 29). Table 2 Comparison between women with HIP in PANDORA and the NT Diabetes in Pregnancy Clinical Register Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 a Including women with GDM and T2DM only. Women without HIP (n = 235) have not been included. Women with T1DM have been excluded from PANDORA (n = 19) and the Clinical Register (n = 29). The baseline characteristics of the women are presented in Table 3 according to diabetes diagnosis and ethnicity. Indigenous women were younger in each of the three diabetes groups (without HIP, GDM and T2DM) compared with their non-Indigenous counterparts. Indigenous women with GDM were also heavier than non-Indigenous women with GDM. There was no difference in the weight gain during pregnancy between Indigenous and non-Indigenous women in all groups. Indices of socioeconomic status were lower among Indigenous women (lower rates of home ownership and lower educational level attainment) compared with non-Indigenous women in all glucose tolerance groups. Indigenous women were also more likely to smoke in pregnancy compared with non-Indigenous women. Table 3 Baseline maternal characteristics Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Total number of women presented in this table, n = 1135, as women with T1DM n = 19 are excluded. Wt, weight; wks, weeks; yrs, years; U/S, ultrasound; IQR, interquartile range, Hb, haemoglobin. a Total number is reduced for specific variables: weight, n = 1097; gestational age of 1st weight, n = 1097; BMI, n = 1093; gestational weight gain, n = 453; housing tenure, n = 1104; tobacco 1st trimester, n = 1135; tobacco 3rd trimester, n = 2017; residence, n = 1135; nulliparity, n = 1135; gestational age 1st ultrasound, n = 1130; folic acid, n = 1135; timing of Hb test, n = 1135; diabetes treatment type n = 901; employment status, n = 1110. Table 3 Baseline maternal characteristics Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Total number of women presented in this table, n = 1135, as women with T1DM n = 19 are excluded. Wt, weight; wks, weeks; yrs, years; U/S, ultrasound; IQR, interquartile range, Hb, haemoglobin. a Total number is reduced for specific variables: weight, n = 1097; gestational age of 1st weight, n = 1097; BMI, n = 1093; gestational weight gain, n = 453; housing tenure, n = 1104; tobacco 1st trimester, n = 1135; tobacco 3rd trimester, n = 2017; residence, n = 1135; nulliparity, n = 1135; gestational age 1st ultrasound, n = 1130; folic acid, n = 1135; timing of Hb test, n = 1135; diabetes treatment type n = 901; employment status, n = 1110. How often are participants being followed-up? Contacts with participants were made during pregnancy, at birth and 6 weeks, 6 months and 2–5 years after birth, with a wide range of data collected (Table 4). Follow-up was performed in person at times or by phone, e-mail survey or via medical records. Pathology test results were obtained from electronic medical records (hospital and Department of Health: Public Health Care where available) or private pathology companies in the NT. To optimize follow-up in the context of challenges of remote and Indigenous health,15 a variety of methods were employed. This included both direct (phone, e-mail, Wave 1) and indirect (medical records and pathology) methods, with different approaches for different participant groups. For example, phone and e-mail follow-up were not feasible for remote Indigenous women. In this case, medical records (indirect) and opportunistic completion of surveys in person were used. Table 4 Study schedule Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • Table 4 Study schedule Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • PANDORA Wave 1 is a sub-study of Aboriginal and Europid mothers from the PANDORA birth cohort with and without HIP and their children aged 18 months to 5 years. It aims to examine cardiometabolic risk factors in mothers and their offspring to identify predictors of later chronic disease including obesity, diabetes and heart disease. Only mothers of Aboriginal or Europid ethnicity (and their children) are eligible for inclusion in this sub-study (mothers of other ethnic groups are not eligible). As PANDORA completed recruitment in February 2017, Wave 1 follow-up is ongoing. Thus, follow-up rate results, outlined in Figure 1, are only for those who have reached 18 months of age. Figure 1 View largeDownload slide PANDORA cohort follow-up. aMiscarriage related to sibling; bone stillbirth related to sibling; cdirect follow-up includes phone, e-mail and Wave 1; dindirect follow-up includes medical records checks and pathology. If a mother or her child dies, the other then only has indirect follow-up but is not withdrawn from the study. Figure 1 View largeDownload slide PANDORA cohort follow-up. aMiscarriage related to sibling; bone stillbirth related to sibling; cdirect follow-up includes phone, e-mail and Wave 1; dindirect follow-up includes medical records checks and pathology. If a mother or her child dies, the other then only has indirect follow-up but is not withdrawn from the study. What has been measured? Pregnancy visits As outlined previously, maternal demographic, clinical and biochemical data were obtained from medical records and questionnaire.16 Oral glucose tolerance test, HbA1c and haemoglobin level were obtained from medical records. Birth visit Maternal birth outcomes were obtained from medical records and questionnaire. Cord blood was collected at birth for measurement of C-peptide, glucose, lipids, high-sensitivity C-reactive protein (hsCRP) and other measures relating to cardiometabolic risk. Birthweight, head circumference and length were recorded at delivery by midwives or obtained from medical records. Detailed neonatal anthropometric measurements (skinfold thickness intriceps, subscapular and flank regions), head and abdominal circumference and length were taken within the first 72 h of birth. Buccal swabs from both the mother and neonate were also collected within 72 h of birth in a subgroup along with cord blood for assessment of epigenetics profile, gene expression (DNA methylation and RNA sequencing) and telomere length. Postpartum follow-up to 6 months The postpartum glycaemic status of women with GDM was obtained via phone, e-mail survey or medical records (hospital and primary care where available). Information was also obtained from private pathology companies servicing the NT. Public hospital laboratories and primary health records were accessed to obtain any investigations related to glucose parameters (OGTT results, fasting plasma glucose, HbA1c, random plasma glucose, HbA1c performed at the point of care). PANDORA Wave 1 (18 months to 5 years postpartum) Maternal data collected include: weight, waist circumference, contraception, bloods, urine and subsequent pregnancy diabetes diagnosis and outcomes. Child assessments include: body size and body fat, height, weight, circumferences (head, waist, mid-upper arm) and skinfold thickness (triceps, supra-iliac, subscapular). Non-invasive assessment of body composition is performed using bioelectrical impedance.17 Venous bloods (glucose, HbA1c, C-peptide, lipids, haemoglobin, hsCRP) are collected from both mother and child for assessment of cardiometabolic health. Aortic intima-media thickness (AIMT, non-invasive marker of vascular health)18 is measured. Bioelectrical impedance and AIMT cannot performed on all community visits, and thus measures are completed on a sub-group only. The developmental risk assessment of the child is undertaken by administering the ASQ-3 developmental screening tool or the ASQ-TRAK (a culturally adapted developmental screening tool for use in the Australian Aboriginal context). The Strengths and Difficulties Questionnaire is only administered to children age 3 years and over.19–23 Feeding practices and nutrition of mother and child are assessed using a dietary assessment tool developed for this context, with visuals and facilitated methodology and assessment of traditional foods largely informed by the PREDIMED dietary screener and additional validated questions on discretionary foods.24–26 What has been found? Key findings and publications We have published a protocol outlining recruitment and data collection in the pregnancy and birth phase of PANDORA.16 Recruitment to the PANDORA cohort was recently completed and several manuscripts detailing key outcomes are in preparation. Maternal antenatal health Indigenous Australian women are at higher risk of developing HIP compared with non-Indigenous Australian women.2 Of potential concern, in addition to HIP, are the multiple factors that may contribute to the disparity in perinatal outcomes between Indigenous and non-Indigenous mothers and babies, such as high rates of cigarette smoking, alcohol consumption, socioeconomic disadvantage and geographical remoteness. In the limited prospective studies in Australia, Indigenous women were reported as more likely to present late (defined as >14 weeks of gestation) for their first antenatal visit than non-Indigenous women.27 In this context, the antenatal period of a pregnancy complicated by hyperglycaemia provides a unique opportunity to educate women with HIP of the importance of prenatal and earlier antenatal care in future pregnancies, so that early intervention in both the mother’s and the baby’s life course can be initiated to reduce future risk of chronic disease.28 In our PANDORA cohort, Indigenous women were less likely to be nulliparous or on folate supplementation, and more likely to smoke in pregnancy than non-Indigenous women. Indigenous women with HIP were more likely to require more intensive diabetes treatment with metformin and insulin than non-Indigenous women (Table 3). Indigenous women had a 3-fold higher risk of presenting later than 14 weeks of gestation for initial antenatal care compared with non-Indigenous women (Figure 2). The relationship between age and the outcome was non-linear and thus age was included as a categorical variable. There was a higher likelihood of late presentation for women <20 years of age [odds ratio (OR) 2.97, 95% confidence interval (CI) 1.35–6.52] as compared with women 25–29 years of age. Employment and education were strongly correlated, and both were strongly associated with late presentation when modelled without one another. Unemployed women as compared with women with a full-time or part-time job were almost twice as likely to present after 14 weeks for their first antenatal visit (OR 1.78, 95% CI 1.04–3.05). Women who had completed high school (completion of Year 12) (OR 0.46, 95% CI 0.27–0.81) and lived in urban areas (OR 0.55, 95% CI 0.32–0.97) were more likely to present earlier for their first antenatal visit. Women who did not own their own home (OR 4.51, 95% CI 1.35–15.04) were four-times more likely to present for their first antenatal visit after 14 weeks. Figure 2 View largeDownload slide Forest plot for antenatal visits >14weeks. Forest plot showing the age-adjusted odds ratio of first antenatal visit >14 weeks by ethnicity and antenatal factors. 95% CIs are shown. BMI, nulliparity, tobacco smoking and alcohol consumption in pregnancy were part of the multivariable model building but their P-values did not reach statistical significance and thus were excluded. Yr, year. aYr 12 refers to completion of high school. Figure 2 View largeDownload slide Forest plot for antenatal visits >14weeks. Forest plot showing the age-adjusted odds ratio of first antenatal visit >14 weeks by ethnicity and antenatal factors. 95% CIs are shown. BMI, nulliparity, tobacco smoking and alcohol consumption in pregnancy were part of the multivariable model building but their P-values did not reach statistical significance and thus were excluded. Yr, year. aYr 12 refers to completion of high school. Our findings extend those of recent Australian studies29,30 as well as data from other high-income countries,31,32 where women from ethnic minority backgrounds and/or socioeconomically disadvantaged groups tend to enter antenatal care at a later gestational age compared with ethnic majority women. This key finding highlights the significant health challenges for Indigenous and ethnic minority populations globally. There is an urgent need to improve access to high quality and culturally appropriate antenatal care, as well as improve pre-conception and inter-pregnancy education for this high-risk population. What are the main strengths and weaknesses? Aboriginal women represent 50% of PANDORA participants, and the cohort will provide valuable and novel data to elucidate causal pathways of diabetes including youth-onset diabetes and intergenerational diabetes in this high-risk population. This population not only faces the burden of high rates of HIP but is also at risk of inadequate nutrition. Hence the detailed neonatal anthropometric data will provide invaluable insight into the contribution of body fat to birthweight in a population experiencing the above double burden, and as previously described as the thin-fat baby phenotype by Yajnik et al.33 in India. In addition, our cohort is unique for the high proportion of mothers with T2DM in pregnancy. The follow-up of infants of mothers with T2DM is a key strength of this cohort, as these are at greatest risk of developing early-onset obesity and T2DM. Hence, we are positioned to address the evidence gap regarding early growth patterns of infants born to mothers with T2DM compared with those born to mothers with and without GDM. This will inform the timing and types of future interventions to prevent or reduce the impact of the intergenerational cycle of disease in the high-risk Indigenous Australian population. Another strength of PANDORA is that recruitment was from the clinical register, thus allowing comparisons to be performed between participants and the broader population. There were no differences between the women on the clinical register and PANDORA in terms of age, Indigenous ethnicity and remote living. The group of women without HIP adds strength to the PANDORA Study as a comparator group (with the women with HIP). This will add perspective to the impact of HIP on the outcomes of the mothers and offspring with HIP, and hence will guide policy makers and researchers to priority areas requiring intervention. The PANDORA Study sits within the NT Diabetes in Pregnancy Partnership, a strong partnership between researchers, policy makers and health services, which includes an intervention to improve our models of care for HIP. Thus we are well placed to translate findings from this study into practice and policy, as well as to inform design of future interventions studies. An evaluation of the perspectives of health professionals of models of care in 2017 reported that the Partnership has improved health professional relationships and communication, as well as facilitated improved integration of quality improvement activities in the NT.8 The Partnership continues to work to improve models of care, with a current intervention to improve postpartum models of care in order to improve maternal health in pregnancy (and thus health before the next pregnancy). Limitations include the need to achieve a balance between the ideal study design and the feasibility of follow-up of families residing in remote Indigenous communities. Some of the challenges of collecting data for this population include their remote location (often inaccessible by road for up to 6 months of the year), limited and unreliable telephone and internet services, frequent name changes of individuals and the high mobility of the population.34 For these reasons, antenatal maternal biospecimens were not collected, and a variety of methods of follow-up are used to maximize follow-up rates (Figure 1). Follow-up rates for other Indigenous Australian cohorts range from 31% at 6 years35 to 86% at age 11 years in the Aboriginal Birth Cohort.36,34 Second, the Clinical Register did not include all women with HIP. We have previously reported that the number of women with HIP on the Clinical Register increased from its commencement in 2012 to 2014, such that in 2014, women on the register represented 75% of those on the Midwives Data Collection for Aboriginal women with GDM and 100% for Aboriginal women with pre-existing diabetes.7 Can I get hold of the data? Where can I find out more? Further information about PANDORA can be obtained via the study website:[ www.dipp.org.au] or by e-mailing the lead principal investigator, Associate Professor Louise Maple-Brown [Louise.Maple-Brown@menzies.edu.au].16 Requests for access to the data and establishment of collaborative projects are considered by the NT DIP Partnership Steering Committee and Editorial Committee. Profile in a nutshell The PANDORA Study is a prospective, observational pregnancy and birth cohort with a focus on metabolic health of Indigenous Australians. Cohort participants are 1140 women with and without HIP and 1170 children, from Northern Territory, Australia; half the participants are Aboriginal. Detailed antenatal maternal demographic, clinical and biochemical data were collected in pregnancy. Perinatal outcomes, cord blood and detailed neonatal anthropometrics were also collected. Follow-up has included collecting data on maternal and child health, breastfeeding, diet, growth and development at 18 months to 5 years of age. Those interested in collaborating with PANDORA should contact Associate Professor Louise Maple-Brown (Louise.Maple-brown@menzies.edu.au) Funding This work was supported by the National Health and Medical Research Council of Australia (NHMRC Partnership Project Grant #1032116, NHMRC #1078333). Additional support (including pilot funding) was received from NHMRC Program Grant #631947. LMB was supported by NHMRC Fellowship #605837 and NHMRC Practitioner Fellowship #1078477; IL was supported by an Australian Postgraduate award and Menzies scholarship; MRS was supported by National Heart Foundation of Australia Future Leader Fellowship #100419; RES is supported by NHMRC Senior Research Fellowship #1038018; JES was supported by NHMRC Fellowship #1079438. Acknowledgements We gratefully acknowledge all PANDORA Study staff and participants, including: Lynice Wood and Liz Davis, as well as NT DIP investigators, partners, staff and clinical reference group, NT health professionals from NT Department of Health hospitals, remote primary health care, Healthy Living NT and Aboriginal Community Controlled Health Organizations. The views expressed in this publication are those of the authors and do not reflect the views of the NHMRC. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. 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A 14-item Mediterranean diet assessment tool and obesity indexes among high-risk subjects: the PREDIMED trial . PLoS One 2012 ; 7 : e43134 . Google Scholar Crossref Search ADS PubMed 25 Gwynn JD , Flood VM , D’Este CA et al. The reliability and validity of a short FFQ among Australian Aboriginal and Torres Strait Islander and non-Indigenous rural children . Public Health Nutr 2011 ; 14 : 388 – 401 . Google Scholar Crossref Search ADS PubMed 26 Burrows TL , Collins K , Watson J et al. Validity of the Australian Recommended Food Score as a diet quality index for Pre-schoolers . Nutr J 2014 ; 13 : 87. Google Scholar Crossref Search ADS PubMed 27 Rumbold AR , Cunningham J. A review of the impact of antenatal care for Australian Indigenous women and attempts to strengthen these services . Matern Child Health J 2008 ; 12 : 83 – 100 . Google Scholar Crossref Search ADS PubMed 28 Sayers S , Boyle J. Indigenous perinatal and neonatal outcomes: a time for preventive strategies . J Paediatr Child Health 2010 ; 46 : 475 – 78 . Google Scholar Crossref Search ADS PubMed 29 AIHW . Aboriginal and Torres Straight Islander Health Performance Framework 2010 Report: Northern Territory . Caberra : Australian Institute of Health and Welfare , 2010 . 30 Trinh L , Rubin G. Late entry to antenatal care in New South Wales, Australia . Reprod Health 2006 ; 3:8 . 31 Rowe RE , Magee H , Quigley MA , Heron P , Askham J , Brocklehurst P. Social and ethnic differences in attendance for antenatal care in England . Public Health 2008 ; 122 : 1363 – 72 . Google Scholar Crossref Search ADS PubMed 32 Posthumus AG , Scholmerich VLN , Steegers EAP , Kawachi I , Denktas S. The association of ethnic minority density with late entry into antenatal care in the Netherlands . PLoS One 2015 ; 10 : e0122720. Google Scholar Crossref Search ADS PubMed 33 Yajnik C , Fall C , Coyaji K et al. Neonatal anthropometry: the thin–fat Indian baby. The Pune maternal nutrition study . Int J Obes Relat Metab Disord 2003 ; 27 : 173 – 80 . Google Scholar Crossref Search ADS PubMed 34 Lawrance M , Sayers SM , Singh GR. Challenges and strategies for cohort retention and data collection in an indigenous population: Australian Aboriginal Birth Cohort . BMC Med Res Methodol 2014 ; 14 : 31. Google Scholar Crossref Search ADS PubMed 35 McDermott RA , Li M , Campbell SK. Incidence of type 2 diabetes in two Indigenous Australian populations: a 6-year follow-up study . Med J Aust 2010 ; 192 : 562 – 65 . Google Scholar PubMed 36 Mackerras DE , Reid A , Sayers SM , Singh GR , Bucens IK , Flynn KA. Growth and morbidity in children in the Aboriginal Birth Cohort Study: the urban-remote differential . Med J Aust 2003 ; 178 : 56 – 60 . Google Scholar PubMed © The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Epidemiology Oxford University Press

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Oxford University Press
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© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
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0300-5771
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1464-3685
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Abstract

Why was the study set up? Type 2 diabetes (T2DM) contributes significantly to the mortality gap between Indigenous and non-Indigenous Australians, with the onset of diabetes occurring at a younger age among Indigenous Australians.1 We respectfully acknowledge the two Indigenous populations of Australia, the Aboriginal and Torres Strait Islander peoples, who are referred to as Indigenous people in this paper. Thus T2DM is increasingly reported in Indigenous children and youth, and also prior to pregnancy among Indigenous women. Indigenous women are 10 times more likely to have T2DM in pregnancy and 1.5 times more likely to have gestational diabetes (GDM) than non-Indigenous women.2 The intergenerational impact of T2DM on Indigenous communities is of great concern, as offspring of an intrauterine environment exposed to hyperglycaemia in pregnancy (HIP) are at significantly higher risk of obesity and diabetes later in life. For example, among Pima Indian peoples, children born after their mother was diagnosed with HIP were reported to have significantly higher body mass index (BMI) and 4-fold higher diabetes risk than their siblings born prior to diagnosis.3 Prevention strategies implemented during early life are likely to be the most effective in addressing this epidemic among Indigenous Australians. In this context, HIP (which includes both GDM and pre-existing type 2 diabetes in pregnancy) may identify a group among Indigenous mothers and children who will specifically benefit from targeted early intervention, to reduce future risk and burden of chronic disease in this high-risk population. The Barker hypothesis proposed that inadequate nutrition in utero and in early infancy contributes to increased chronic disease risk later in life, including diabetes.4 This is known as the fetal programming or Developmental Origins of Health and Disease hypothesis. Paradoxically, the HIP that contributes to over-nutrition in the developing offspring is also associated with higher chronic disease risk.5,6 Indigenous communities in the Northern Territory (NT) experience the double burden of increasing HIP rates and inadequate nutrition. Hence it is pivotal to understand the complex interplay of these issues on offspring outcomes, to inform clinical guidelines in order to reduce future risk of chronic disease in the high-risk Indigenous Australian population. The PANDORA Study is a prospective, observational pregnancy and birth cohort study of 1140 women and 1170 children, with detailed pregnancy and birth data collected, plus neonatal anthropometric measurements and matched biospecimens. The primary aim of the study is to assess demographic, clinical, socioeconomic and biochemical factors that may contribute to key maternal and neonatal birth outcomes associated with HIP in the high-risk Indigenous Australian population. The PANDORA Study also assesses relevant long-term clinical and cardiometabolic outcomes for both mothers and their infants, to provide reliable information around future health risk. The follow-up of mothers and children in PANDORA is planned with current consent for follow-up until 12 years of age/postpartum. Following this, participants will be approached for assent/consent for ongoing follow-up. The PANDORA Study sits within the Northern Territory (NT) Diabetes in Pregnancy Partnership that has established the NT Diabetes in Pregnancy Clinical Register and has worked with health services to improve HIP models of care, contributing to improved integration, communication and care coordination.7,8 Who is in the sample? The NT of Australia covers a large geographical area with a relatively small population of approximately 240 000.9 This population is the youngest in Australia with a median age of 31.8 years, which is 6 years younger than the national median. The NT also has the highest proportion of Aboriginal and Torres Strait Islander people at 30%, representing 10% of the total Australian Indigenous population. In 2013, 31% of babies born to NT mothers were Indigenous compared with 6% among all babies born in Australia.10,11 Most Indigenous women (approximately 60%) live in rural or remote NT and receive antenatal care in their own communities.10 Local midwives, remote medical practitioners and general practitioner obstetricians provide antenatal care with support from outreach specialist obstetricians, allied health professionals and multidisciplinary input as available. Of all births in the NT, 98% occur within five hospitals. Women diagnosed with HIP were invited from the NT Diabetes in Pregnancy Clinical Register to participate in PANDORA. Women without HIP were recruited from antenatal clinics. During the course of the study, the GDM diagnostic guidelines were changing both in Australia and internationally. Between 2012 and 2014, there was a gradual increase in implementation of new guidelines throughout the NT. Hence women with GDM were diagnosed by either the 1999 Australian Diabetes in Pregnancy Society (ADIPS)12 guidelines, or a universal 75-g oral glucose tolerance test (OGTT) and revised glucose cut-points as recommended by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG)13 and the World Health Organization (WHO).14 Of the cohort, 10.3% satisfied only the ADIPS glucose thresholds, 11.5% satisfied only the WHO glucose thresholds and 76.6% satisfied both. Of note, Indigenous women with GDM in PANDORA were more likely to have oral glucose tolerance test (OGTT) results suggestive of possible undiagnosed T2DM (Indigenous vs non-Indigenous women, 19.3% vs 7.2%, P < 0.001, defined as fasting plasma glucose  ≥ 7.0 mmol/L or 2-h plasma glucose  ≥ 11.1 mmol/L or HbA1c  ≥ 6.5%).14 The PANDORA eligibility criteria are outlined in Table 1. The 5-year recruitment phase was completed in February 2017. A comparison of women with HIP in PANDORA and women on the Clinical Register is presented in Table 2. Note that some remote Indigenous women were ineligible for inclusion in the study before March 2015, as community consultation (a prerequisite for participation) was not completed with some Aboriginal Community Controlled Health Organizations. Targeted recruitment occurred in 2016. The PANDORA cohort at birth comprises 1140 women (905 with HIP and 235 without, 46.5% Indigenous women) and 1170 babies (including 16 twin sets). Table 1 Eligibility criteria Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years NT, Northern Territory. a Women with GDM were diagnosed by either the 1999 Australian Diabetes in Pregnancy Society (ADIPS)12 guidelines, or a universal 75-g oral glucose tolerance test (OGTT) and revised glucose cut-points as recommended by International Association of the Diabetes and Pregnancy Study Groups (IADPSG)13 and the World Health Organization (WHO).14 Table 1 Eligibility criteria Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years Eligibility crieria Hyperglycaemia in pregnancya group Without HIP group Inclusion criteria Women with any diabetes in pregnancy: T1DM, T2DM and GDM All ethnicities Birthing in the NT or permanent resident of the NT who is transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Birthing in the NT or permanent resident of the NT transferred interstate for birth (due to medical reasons) Planning to reside in the NT for at least 2 years after the birth Has had an OGTT after 24 weeks of gestation Aboriginal or Europid ethnicity Exclusion criteria 1. Age <16 years 2. Normal 7-g OGTT Any type of diabetes that is current Abnormal 7-g OGTT Age <16 years NT, Northern Territory. a Women with GDM were diagnosed by either the 1999 Australian Diabetes in Pregnancy Society (ADIPS)12 guidelines, or a universal 75-g oral glucose tolerance test (OGTT) and revised glucose cut-points as recommended by International Association of the Diabetes and Pregnancy Study Groups (IADPSG)13 and the World Health Organization (WHO).14 Table 2 Comparison between women with HIP in PANDORA and the NT Diabetes in Pregnancy Clinical Register Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 a Including women with GDM and T2DM only. Women without HIP (n = 235) have not been included. Women with T1DM have been excluded from PANDORA (n = 19) and the Clinical Register (n = 29). Table 2 Comparison between women with HIP in PANDORA and the NT Diabetes in Pregnancy Clinical Register Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 Characteristics PANDORAa (n = 900) Clinical Register (n = 1656) P-value Age (years) 30.9 (5.7) 30.5 (5.8) 0.09 Indigenous ethnicity (%) 425 (47.2) 819 (49.5) 0.41 Remote living (%) 429 (62.2) 693 (41.9) 0.10 a Including women with GDM and T2DM only. Women without HIP (n = 235) have not been included. Women with T1DM have been excluded from PANDORA (n = 19) and the Clinical Register (n = 29). The baseline characteristics of the women are presented in Table 3 according to diabetes diagnosis and ethnicity. Indigenous women were younger in each of the three diabetes groups (without HIP, GDM and T2DM) compared with their non-Indigenous counterparts. Indigenous women with GDM were also heavier than non-Indigenous women with GDM. There was no difference in the weight gain during pregnancy between Indigenous and non-Indigenous women in all groups. Indices of socioeconomic status were lower among Indigenous women (lower rates of home ownership and lower educational level attainment) compared with non-Indigenous women in all glucose tolerance groups. Indigenous women were also more likely to smoke in pregnancy compared with non-Indigenous women. Table 3 Baseline maternal characteristics Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Total number of women presented in this table, n = 1135, as women with T1DM n = 19 are excluded. Wt, weight; wks, weeks; yrs, years; U/S, ultrasound; IQR, interquartile range, Hb, haemoglobin. a Total number is reduced for specific variables: weight, n = 1097; gestational age of 1st weight, n = 1097; BMI, n = 1093; gestational weight gain, n = 453; housing tenure, n = 1104; tobacco 1st trimester, n = 1135; tobacco 3rd trimester, n = 2017; residence, n = 1135; nulliparity, n = 1135; gestational age 1st ultrasound, n = 1130; folic acid, n = 1135; timing of Hb test, n = 1135; diabetes treatment type n = 901; employment status, n = 1110. Table 3 Baseline maternal characteristics Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Characteristics Without HIP GDM T2DM Non-Indigenous (n = 118) Indigenous (n = 117) P-value Non-Indigenous (n = 452) Indigenous (n = 273) P-value Non-Indigenous (n = 23) Indigenous (n = 152) P-value Mean age (yrs) 30.4 (5.1) 25.1 (4.7) <0.001 31.6 (5.1) 29.3 (6.2) <0.001 33.6 (5.6) 31.1 (5.6) 0.049 Weight (kg)a 73.1 (16.3) 66.0 (16.2) <0.001 74.2 (19.0) 77.5 (22.0) 0.037 79.7 (24.7) 84.4 (17.3) 0.26  Gestational age at 1st weight (weeks) 16.0 (4.8) 14.9 (7.3) 0.16 15.5 (5.3) 14.6 (7.4) 0.08 11.1 (4.0) 13.5 (7.4) 0.12 BMIa, kg/m2 26.0 (5.2) 24.8 (6.0) 0.13 28.0 (6.3) 29.2 (7.3) 0.029 30.3 (7.6) 31.3 (5.7) 0.48 Gestational weight gain (kg)a 16.8 (9.7) 13.8 (7.0) 0.12 11.2 (7.9) 10.0 (6.7) 0.26 10.3 (9.9) 8.41 (11.1) 0.51 House tenure (%)  Owned 54 (46.2) 8 (7.1) <0.001 149 (33.7) 18 (6.6) <0.001 7 (31.8) 1 (1.0) <0.001 Education (%)  ≤Yr 9 2 (1.7) 13 (11.4) 11 (2.5) 49 (18.0) 2 (9.1) 43 (39.3)  Yr 10/11 10 (8.5) 42 (36.8) 37 (8.4) 91 (33.3) 53 (36.1) 3 (13.6)  Yr 12 62 (52.5) 55 (48.3) 209 (47.4) 115 (42.1) 8 (36.4) 51 (34.7)  Tertiary 44 (37.3) 4(3.5) <0.001 184 (41.7) 6 (2.2) <0.001 9 (40.9) 0 (0) <0.001 Tobacco smoking (%)  1st trimester 20 (17) 46 (37.6) <0.001 47 (10.4) 118 (43.2) <0.001 1 (4.4) 58 (38.2) 0.001  3rd trimester 9 (7.6) 36 (30.8) <0.001 22 (4.9) 103 (37.7) <0.001 1 (4.4) 45 (29.6) 0.010 Residence (%)  Regional/remote 1(1) 80 (68.4) <0.001 28 (6.2) 195 (71.4) <0.001 1 (4.4) 124 (81.6)) <0.001 Nulliparity (%) 61 (51.7) 49 (41.9) 0.037 216 (47.8) 59 (21.6) <0.001 9 (39.1) 21 (13.8) 0.006 Gestation 1st U/S (median wk, IQR) 8.2 [7.1–10.9] 12.1 [8.4–16.3] <0.001 9 [7.3–12.4] 11.6 [8.4–17.9] <0.001 10.1 [7.7–12.9] 11.1 [8–16.6] 0.33  <14 wks 111 (94.1) 76 (65.0) 408 (90.9) 173 (63.8) 20 (87) 103 (67.6)  14.1–20 wks 4 (3.4) 20 (17.1) 25 (5.6) 45 (16.6) 0 (0) 22 (14.5)  20.1 wks 3 (2.5) 21 (18.0) <0.001 16 (3.6) 53 (19.6) <0.001 3 (13) 27 (17.8) 0.098 Folic acid (%) 122 (93.1) 83 (70.3) <0.001 414 (92.6) 179 (65.8) <0.001 22 (95.7) 97 (66.9) 0.019 Timing of Hb test  Gestational age (wks) 5.7 [4.9–8.7] 9.6 [6.6–17.1] <0.001 7 [5.4–11.4] 9.1 [6.6–15.6] <0.001 7.0 [5.6–10.1] 8.0 [5.9–14.7] 0.27  <14 wks 117 (99.2) 89 (76.1) <0.001 436 (96.5) 216 (79.1) <0.001 23 (100) 119 (78.3) 0.015 Diabetes treatment type (%)  Diet only 220 (48.7) 99 (36.3) 1 (4.4) 2 (1.3)  Metformin only 53 (11.7) 75 (27.5) 1 (4.4) 24 (15.8)  Insulin only 121 (26.8) 28 (10.3) 8 (34.8) 17 (11.2)  Metformin & insulin 56 (12.8) 71 (26.0) <0.001 13 (56.5) 109 (71.7) 0.010 Employment status  Employed full-time or part-time 87 (73.7) 30 (36.6) <0.001 280 (63.4) 61 (22.9) <0.001 15 (68.2) 16 (10.7) <0.001 Total number of women presented in this table, n = 1135, as women with T1DM n = 19 are excluded. Wt, weight; wks, weeks; yrs, years; U/S, ultrasound; IQR, interquartile range, Hb, haemoglobin. a Total number is reduced for specific variables: weight, n = 1097; gestational age of 1st weight, n = 1097; BMI, n = 1093; gestational weight gain, n = 453; housing tenure, n = 1104; tobacco 1st trimester, n = 1135; tobacco 3rd trimester, n = 2017; residence, n = 1135; nulliparity, n = 1135; gestational age 1st ultrasound, n = 1130; folic acid, n = 1135; timing of Hb test, n = 1135; diabetes treatment type n = 901; employment status, n = 1110. How often are participants being followed-up? Contacts with participants were made during pregnancy, at birth and 6 weeks, 6 months and 2–5 years after birth, with a wide range of data collected (Table 4). Follow-up was performed in person at times or by phone, e-mail survey or via medical records. Pathology test results were obtained from electronic medical records (hospital and Department of Health: Public Health Care where available) or private pathology companies in the NT. To optimize follow-up in the context of challenges of remote and Indigenous health,15 a variety of methods were employed. This included both direct (phone, e-mail, Wave 1) and indirect (medical records and pathology) methods, with different approaches for different participant groups. For example, phone and e-mail follow-up were not feasible for remote Indigenous women. In this case, medical records (indirect) and opportunistic completion of surveys in person were used. Table 4 Study schedule Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • Table 4 Study schedule Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • Pregnancy Infancy (months) Childhood (years) Antenatal Postnatal Birth 6 weeks 6 12–24 2–5 Questionnaires  Mother’s health, medication • • • • • •  Mother's mental health (PHQ-9) • •  Child’s health, medications • • •  Breastfeeding, child diet • • • •  Family medical history, demographics • •  Child’s growth (medical records) • • • •  Child’s developmental risk • Physical measures  Mother’s anthropometry • •  Mother’s blood pressure • •  Child’s anthropometry • •  Bioelectrical impedance (mother & child) •  Child’s aortic intima-media thickness • Biological samples  Cord blood •  Venous blood (mother & child) •  Buccal swabs (mother & child) • •  Stool (child) • •  Blood for epigenetics • • PANDORA Wave 1 is a sub-study of Aboriginal and Europid mothers from the PANDORA birth cohort with and without HIP and their children aged 18 months to 5 years. It aims to examine cardiometabolic risk factors in mothers and their offspring to identify predictors of later chronic disease including obesity, diabetes and heart disease. Only mothers of Aboriginal or Europid ethnicity (and their children) are eligible for inclusion in this sub-study (mothers of other ethnic groups are not eligible). As PANDORA completed recruitment in February 2017, Wave 1 follow-up is ongoing. Thus, follow-up rate results, outlined in Figure 1, are only for those who have reached 18 months of age. Figure 1 View largeDownload slide PANDORA cohort follow-up. aMiscarriage related to sibling; bone stillbirth related to sibling; cdirect follow-up includes phone, e-mail and Wave 1; dindirect follow-up includes medical records checks and pathology. If a mother or her child dies, the other then only has indirect follow-up but is not withdrawn from the study. Figure 1 View largeDownload slide PANDORA cohort follow-up. aMiscarriage related to sibling; bone stillbirth related to sibling; cdirect follow-up includes phone, e-mail and Wave 1; dindirect follow-up includes medical records checks and pathology. If a mother or her child dies, the other then only has indirect follow-up but is not withdrawn from the study. What has been measured? Pregnancy visits As outlined previously, maternal demographic, clinical and biochemical data were obtained from medical records and questionnaire.16 Oral glucose tolerance test, HbA1c and haemoglobin level were obtained from medical records. Birth visit Maternal birth outcomes were obtained from medical records and questionnaire. Cord blood was collected at birth for measurement of C-peptide, glucose, lipids, high-sensitivity C-reactive protein (hsCRP) and other measures relating to cardiometabolic risk. Birthweight, head circumference and length were recorded at delivery by midwives or obtained from medical records. Detailed neonatal anthropometric measurements (skinfold thickness intriceps, subscapular and flank regions), head and abdominal circumference and length were taken within the first 72 h of birth. Buccal swabs from both the mother and neonate were also collected within 72 h of birth in a subgroup along with cord blood for assessment of epigenetics profile, gene expression (DNA methylation and RNA sequencing) and telomere length. Postpartum follow-up to 6 months The postpartum glycaemic status of women with GDM was obtained via phone, e-mail survey or medical records (hospital and primary care where available). Information was also obtained from private pathology companies servicing the NT. Public hospital laboratories and primary health records were accessed to obtain any investigations related to glucose parameters (OGTT results, fasting plasma glucose, HbA1c, random plasma glucose, HbA1c performed at the point of care). PANDORA Wave 1 (18 months to 5 years postpartum) Maternal data collected include: weight, waist circumference, contraception, bloods, urine and subsequent pregnancy diabetes diagnosis and outcomes. Child assessments include: body size and body fat, height, weight, circumferences (head, waist, mid-upper arm) and skinfold thickness (triceps, supra-iliac, subscapular). Non-invasive assessment of body composition is performed using bioelectrical impedance.17 Venous bloods (glucose, HbA1c, C-peptide, lipids, haemoglobin, hsCRP) are collected from both mother and child for assessment of cardiometabolic health. Aortic intima-media thickness (AIMT, non-invasive marker of vascular health)18 is measured. Bioelectrical impedance and AIMT cannot performed on all community visits, and thus measures are completed on a sub-group only. The developmental risk assessment of the child is undertaken by administering the ASQ-3 developmental screening tool or the ASQ-TRAK (a culturally adapted developmental screening tool for use in the Australian Aboriginal context). The Strengths and Difficulties Questionnaire is only administered to children age 3 years and over.19–23 Feeding practices and nutrition of mother and child are assessed using a dietary assessment tool developed for this context, with visuals and facilitated methodology and assessment of traditional foods largely informed by the PREDIMED dietary screener and additional validated questions on discretionary foods.24–26 What has been found? Key findings and publications We have published a protocol outlining recruitment and data collection in the pregnancy and birth phase of PANDORA.16 Recruitment to the PANDORA cohort was recently completed and several manuscripts detailing key outcomes are in preparation. Maternal antenatal health Indigenous Australian women are at higher risk of developing HIP compared with non-Indigenous Australian women.2 Of potential concern, in addition to HIP, are the multiple factors that may contribute to the disparity in perinatal outcomes between Indigenous and non-Indigenous mothers and babies, such as high rates of cigarette smoking, alcohol consumption, socioeconomic disadvantage and geographical remoteness. In the limited prospective studies in Australia, Indigenous women were reported as more likely to present late (defined as >14 weeks of gestation) for their first antenatal visit than non-Indigenous women.27 In this context, the antenatal period of a pregnancy complicated by hyperglycaemia provides a unique opportunity to educate women with HIP of the importance of prenatal and earlier antenatal care in future pregnancies, so that early intervention in both the mother’s and the baby’s life course can be initiated to reduce future risk of chronic disease.28 In our PANDORA cohort, Indigenous women were less likely to be nulliparous or on folate supplementation, and more likely to smoke in pregnancy than non-Indigenous women. Indigenous women with HIP were more likely to require more intensive diabetes treatment with metformin and insulin than non-Indigenous women (Table 3). Indigenous women had a 3-fold higher risk of presenting later than 14 weeks of gestation for initial antenatal care compared with non-Indigenous women (Figure 2). The relationship between age and the outcome was non-linear and thus age was included as a categorical variable. There was a higher likelihood of late presentation for women <20 years of age [odds ratio (OR) 2.97, 95% confidence interval (CI) 1.35–6.52] as compared with women 25–29 years of age. Employment and education were strongly correlated, and both were strongly associated with late presentation when modelled without one another. Unemployed women as compared with women with a full-time or part-time job were almost twice as likely to present after 14 weeks for their first antenatal visit (OR 1.78, 95% CI 1.04–3.05). Women who had completed high school (completion of Year 12) (OR 0.46, 95% CI 0.27–0.81) and lived in urban areas (OR 0.55, 95% CI 0.32–0.97) were more likely to present earlier for their first antenatal visit. Women who did not own their own home (OR 4.51, 95% CI 1.35–15.04) were four-times more likely to present for their first antenatal visit after 14 weeks. Figure 2 View largeDownload slide Forest plot for antenatal visits >14weeks. Forest plot showing the age-adjusted odds ratio of first antenatal visit >14 weeks by ethnicity and antenatal factors. 95% CIs are shown. BMI, nulliparity, tobacco smoking and alcohol consumption in pregnancy were part of the multivariable model building but their P-values did not reach statistical significance and thus were excluded. Yr, year. aYr 12 refers to completion of high school. Figure 2 View largeDownload slide Forest plot for antenatal visits >14weeks. Forest plot showing the age-adjusted odds ratio of first antenatal visit >14 weeks by ethnicity and antenatal factors. 95% CIs are shown. BMI, nulliparity, tobacco smoking and alcohol consumption in pregnancy were part of the multivariable model building but their P-values did not reach statistical significance and thus were excluded. Yr, year. aYr 12 refers to completion of high school. Our findings extend those of recent Australian studies29,30 as well as data from other high-income countries,31,32 where women from ethnic minority backgrounds and/or socioeconomically disadvantaged groups tend to enter antenatal care at a later gestational age compared with ethnic majority women. This key finding highlights the significant health challenges for Indigenous and ethnic minority populations globally. There is an urgent need to improve access to high quality and culturally appropriate antenatal care, as well as improve pre-conception and inter-pregnancy education for this high-risk population. What are the main strengths and weaknesses? Aboriginal women represent 50% of PANDORA participants, and the cohort will provide valuable and novel data to elucidate causal pathways of diabetes including youth-onset diabetes and intergenerational diabetes in this high-risk population. This population not only faces the burden of high rates of HIP but is also at risk of inadequate nutrition. Hence the detailed neonatal anthropometric data will provide invaluable insight into the contribution of body fat to birthweight in a population experiencing the above double burden, and as previously described as the thin-fat baby phenotype by Yajnik et al.33 in India. In addition, our cohort is unique for the high proportion of mothers with T2DM in pregnancy. The follow-up of infants of mothers with T2DM is a key strength of this cohort, as these are at greatest risk of developing early-onset obesity and T2DM. Hence, we are positioned to address the evidence gap regarding early growth patterns of infants born to mothers with T2DM compared with those born to mothers with and without GDM. This will inform the timing and types of future interventions to prevent or reduce the impact of the intergenerational cycle of disease in the high-risk Indigenous Australian population. Another strength of PANDORA is that recruitment was from the clinical register, thus allowing comparisons to be performed between participants and the broader population. There were no differences between the women on the clinical register and PANDORA in terms of age, Indigenous ethnicity and remote living. The group of women without HIP adds strength to the PANDORA Study as a comparator group (with the women with HIP). This will add perspective to the impact of HIP on the outcomes of the mothers and offspring with HIP, and hence will guide policy makers and researchers to priority areas requiring intervention. The PANDORA Study sits within the NT Diabetes in Pregnancy Partnership, a strong partnership between researchers, policy makers and health services, which includes an intervention to improve our models of care for HIP. Thus we are well placed to translate findings from this study into practice and policy, as well as to inform design of future interventions studies. An evaluation of the perspectives of health professionals of models of care in 2017 reported that the Partnership has improved health professional relationships and communication, as well as facilitated improved integration of quality improvement activities in the NT.8 The Partnership continues to work to improve models of care, with a current intervention to improve postpartum models of care in order to improve maternal health in pregnancy (and thus health before the next pregnancy). Limitations include the need to achieve a balance between the ideal study design and the feasibility of follow-up of families residing in remote Indigenous communities. Some of the challenges of collecting data for this population include their remote location (often inaccessible by road for up to 6 months of the year), limited and unreliable telephone and internet services, frequent name changes of individuals and the high mobility of the population.34 For these reasons, antenatal maternal biospecimens were not collected, and a variety of methods of follow-up are used to maximize follow-up rates (Figure 1). Follow-up rates for other Indigenous Australian cohorts range from 31% at 6 years35 to 86% at age 11 years in the Aboriginal Birth Cohort.36,34 Second, the Clinical Register did not include all women with HIP. We have previously reported that the number of women with HIP on the Clinical Register increased from its commencement in 2012 to 2014, such that in 2014, women on the register represented 75% of those on the Midwives Data Collection for Aboriginal women with GDM and 100% for Aboriginal women with pre-existing diabetes.7 Can I get hold of the data? Where can I find out more? Further information about PANDORA can be obtained via the study website:[ www.dipp.org.au] or by e-mailing the lead principal investigator, Associate Professor Louise Maple-Brown [Louise.Maple-Brown@menzies.edu.au].16 Requests for access to the data and establishment of collaborative projects are considered by the NT DIP Partnership Steering Committee and Editorial Committee. Profile in a nutshell The PANDORA Study is a prospective, observational pregnancy and birth cohort with a focus on metabolic health of Indigenous Australians. Cohort participants are 1140 women with and without HIP and 1170 children, from Northern Territory, Australia; half the participants are Aboriginal. Detailed antenatal maternal demographic, clinical and biochemical data were collected in pregnancy. Perinatal outcomes, cord blood and detailed neonatal anthropometrics were also collected. Follow-up has included collecting data on maternal and child health, breastfeeding, diet, growth and development at 18 months to 5 years of age. Those interested in collaborating with PANDORA should contact Associate Professor Louise Maple-Brown (Louise.Maple-brown@menzies.edu.au) Funding This work was supported by the National Health and Medical Research Council of Australia (NHMRC Partnership Project Grant #1032116, NHMRC #1078333). Additional support (including pilot funding) was received from NHMRC Program Grant #631947. LMB was supported by NHMRC Fellowship #605837 and NHMRC Practitioner Fellowship #1078477; IL was supported by an Australian Postgraduate award and Menzies scholarship; MRS was supported by National Heart Foundation of Australia Future Leader Fellowship #100419; RES is supported by NHMRC Senior Research Fellowship #1038018; JES was supported by NHMRC Fellowship #1079438. Acknowledgements We gratefully acknowledge all PANDORA Study staff and participants, including: Lynice Wood and Liz Davis, as well as NT DIP investigators, partners, staff and clinical reference group, NT health professionals from NT Department of Health hospitals, remote primary health care, Healthy Living NT and Aboriginal Community Controlled Health Organizations. The views expressed in this publication are those of the authors and do not reflect the views of the NHMRC. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. 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Published by Oxford University Press on behalf of the International Epidemiological Association This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

International Journal of EpidemiologyOxford University Press

Published: Aug 1, 2018

References

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